Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids

Human cardiac organoids closely replicate the architecture and function of the human heart, offering a potential accurate platform for studying aging cardiomyopathy. Senolytics have shown potential in addressing age-related pathologies. However, their potential to reverse aging-related human cardiomyopathy remains largely unexplored. We employed human iPSC-derived cardiac organoids (hCardioids) to model doxorubicin-induced cardiomyopathy in an aged context. hCardioids were treated with doxorubicin (DOXO) and subsequently with a combination of two senolytics: dasatinib (D) and quercetin (Q). DOXO-treated hCardioids exhibited significantly increased oxidative stress, DNA damage (pH2AX), cellular senescence (p16) and decreased cell proliferation associated with a senescence-associated secretory phenotype (SASP). DOXO-treated hCardioids were considerably deprived of cardiac progenitors and displayed reduced cardiomyocyte proliferation as well as contractility. These distinctive aging-associated characteristics were confirmed by global RNA-sequencing analysis. Treatment with D+Q reversed these effects, reducing oxidative stress and senescence markers, alleviating SASP, and restoring hCardioids viability and function Additionally, senolytics replenished cardiac progenitors and reversed the cardiomyocyte proliferation deficit. Doxorubicin triggers an age-associated phenotype in hCardioids representing a reliable model of aged cardiomyopathy. Senescence is a key mechanism of the aged phenotype as senolytics rejuvenated aged hCardioids restoring their structure and function while reverting the age-associated regenerative deficit.